Lung cancer is one of the leading causes of cancer deaths in the US with 5 year survival rate of ~15% due to the lack of specificity, poor efficacy, and side effects associated with current therapies. The lung cancer incidences are highest in African Americans, American Indians/Alaska Natives, and Pacific Islanders. The non- small cell lung cancer (NSCLC) is most prevalent (~80% occurrence) among lung cancer patient. NSCLC has wide molecular heterogeneity, which mandates simultaneous targeting of multiple pathways. Vascular endothelial growth factor (VEGF) gene over-expression (in ~90% of NSCLC's) is associated with growth, survival, and angiogenesis. The use of VEGF antibodies to block VEGF has been limited due to their non- specificity, poor efficacy and adverse effects. In this line, silencing VEGF using VEGF-siRNA (siRNA-V) will be an effective option, however, the clinical utility of siRNA has been hampered due to non-specific effect, poor cell permeation and rapid in vivo elimination. The use of nanocarriers for siRNA-V delivery will help to overcome these issues. Furthermore, PI3K/mTOR was found to be predominantly activated in NSCLC, additionally, mTOR inhibition results in compensatory activation of Akt (a promoter of cell survival and proliferation). Hence, simultaneous targeting of mTOR and Akt along with VEGF silencing will pave the way for more effective NSCLC therapy. PF-04691502 (PF0) is a potent PI3K/mTOR/AKT inhibitor. Targeting mTOR/AKT pathway using PF0 along with VEGF silencing will complement the clinical potential of these bioactives against NSCLC. LHRH receptors are over-expressed on NSCLC cells with restricted expression on normal tissues. For the first time, we are herewith proposing the development of biodegradable, LHRH receptor-targeted PEGylated hybrid nanocarrier (HNC) for the simultaneous targeted delivery of siRNA-V and PF0 (HNC-VP-L) to NSCLC. We hypothesize that the development of stable, LHRH receptor-guided PEGylated albumin-chitosan based hybrid nanocarriers will deliver the synergistically-acting siRNA-V and PF0 in a targeted fashion to NSCLC tumors and will result in a significant improvement of anticancer activity, at lower doses, while overcoming adverse effects. We plan to test our hypothesis by following specific aims: Aim 1: To evaluate the combination effect of siRNA-V and PF0; development and evaluation of HNC-VP-L; Aim 2: To evaluate the in vivo efficacy of HNC-VP-L in nude mice; and Aim 3: To elucidate mechanism, evaluate metastasis and toxicological parameters. We plan to utilize LHRH receptor positive and LHRH receptor negative tumor cell based in vitro as well as in vivo models (xenograft and orthotropic) to investigate the targeting potential of developed nan carriers. Our approach aims at developing a more effective treatment modality for the treatment of NSCLC to reduce the burden of lung cancer disparity. The long term goal is to advance this novel delivery concept to the clinic level. We will be able to establish the first nan carrier based extramural cancer program in the state of Hawaii and train the unrepresented students through this project.